Session Summaries from the ESH-iCMLf 28th Annual John Goldman Conference on CML: Biology and Therapy - Session 5

Scientific Session: Treatment-free remission

Chair: Delphine Réa (Paris)

Treatment-free remission (TFR) has become an important goal in the management of CML, but how can more patients achieve and sustain remission without treatment?
This scientific session explored opportunities to improve TFR success through better patient selection, repeated discontinuation attempts and gradual TKI dose reduction. The presentations also provided evidence that long-term TFR can persist despite detectable residual disease, supporting the concept of an operational cure.

Across the session, a central message emerged: current TFR success rates do not necessarily represent the ceiling. Advances in understanding molecular and immune predictors, together with more individualised discontinuation strategies, may enable more patients to achieve sustained TFR while maintaining safety and quality of life.

Our key takeaways from the presentations:

Keynote presentation

Have we reached a ceiling in TFR success?
Speaker: Susanne Saussele (Mannheim)

“So I think we have not reached the ceiling. [...] With longer follow-up and the possibility of second or even third stop attempts, I think this will increase the number of patients achieving TFR in the future.” - Susanne Saussele

Key points:

• Current TFR success rates: Early TFR studies reported approximately 40% success among eligible patients, translating into an estimated 20–30% of the overall CML population achieving TFR.
  Long-term potential: Prospective studies support these estimates, but longer follow-up and additional discontinuation opportunities could increase the proportion of patients achieving TFR over time.
  Repeated attempts: A first unsuccessful TFR attempt does not necessarily represent the end of treatment discontinuation attempts. Second and potentially third attempts offer additional opportunities for sustained remission.
  Early response: Faster BCR::ABL1 reduction and achievement of deep molecular response (MR4.5) are important predictors of future TFR eligibility. Findings from the JALSG CML212 study support earlier treatment optimisation.
  Immune mechanisms: Better understanding of immune surveillance, particularly NK-cell activity and interactions with residual leukemic stem cells, may provide new opportunities to improve TFR success.
  Individualised approaches: Some patients without optimal conventional TFR eligibility factors may maintain remission after discontinuation, although such approaches require careful monitoring and further evidence.

Presentation 1

Sustained treatment-free remission beyond 10 years in chronic myeloid leukemia: a real-world cohort supporting the concept of operational cure
Speaker: François-Xavier Mahon (Bordeaux)

“The persistence of leukemic cells does not necessarily mean disease recurrence.” - François-Xavier Mahon

Key points:

• Long-term remission: A retrospective real-world cohort of 62 patients who had already maintained TFR for at least 10 years demonstrated a median recorded TFR duration of 13.15 years (range 10.1–30.8 years), providing insights into sustained disease control.

• Treatment history: Long-term TFR was observed across different treatment histories: interferon-alpha alone (11 patients), interferon followed by TKI treatment (28 patients), and TKI treatment alone (23 patients).

• Deep responses: At the last follow-up, 53 patients were in MR5, eight in MR 4.5 and one in MR4, demonstrating sustained deep molecular responses across treatment groups.

• Residual disease: Some patients maintained TFR despite detectable or fluctuating BCR::ABL1 levels, indicating that molecular residual disease does not necessarily lead to clinical relapse.

• Operational cure: These observations support the concept of operational cure, in which CML remains controlled without ongoing treatment, even when residual leukemic cells may persist.

• Future research: The selected retrospective cohort and changes in molecular monitoring over time limit broader conclusions. Further research is needed to identify which BCR::ABL1-positive cells persist and what prevents disease re-establishment.

Presentation 2

High rates of successful second stop attempts in patients with chronic myeloid leukemia: results of the NAUT trial
Speaker: Susanne Saussele (Mannheim)
 

“The trial demonstrates that a relevant proportion of patients can stop a second time after a first unsuccessful TFR approach.” - Susanne Saussele

Key points:

• Second attempts: The prospective, multicentre NAUT trial investigated whether patients who experienced molecular recurrence after an earlier TFR attempt could successfully discontinue treatment again following TKI retreatment.

• Interim efficacy: At the planned interim analysis, molecular recurrence-free survival was 58% at 12 months, with 35 of 61 evaluable patients remaining in TFR. Longer-term results are pending.

• Response recovery: Among 25 patients who restarted TKI treatment following molecular recurrence, 24 rapidly regained at least MR4; one patient was lost to follow-up.

• Safety: No new safety signals were observed with nilotinib treatment, and no disease progression or deaths were reported in the interim analysis.

• Adverse events: More than 40% of patients experienced cardiovascular adverse events (despite ESC inclusion criteria), predominantly arterial hypertesion, which were rarely above grade 2. Nearly half reported musculoskeletal symptoms before discontinuation.

• Clinical implications: These interim findings suggest that a substantial proportion of patients may achieve TFR after a previous unsuccessful attempt. Longer-term follow-up is needed to confirm the durability of remission and identify predictors of success.

Presentation 3

Discontinuation of tyrosine kinase inhibitors following prior two-step dose reduction: results of the Czech nationwide HALF study in patients with chronic myeloid leukemia
Speaker: Daniela Žáčková (Brno)

“We can use this dose reduction period like a window [...] for further enhancement of prognostication and for decision-making.” - Daniela Žáčková

Key points:

• Two-step dose reduction: The HALF study evaluated a two-step TKI dose-reduction strategy before discontinuation: six months at half the standard dose, followed by six months of the reduced dose administered every other day.

• Encouraging efficacy: Among 207 enrolled patients, molecular recurrence-free survival was 69.8% at 24 months and approximately 65% at 36 months after study entry, including the 12-month dose-reduction period.

• Safety: Patients who lost major molecular response (MMR) regained it promptly after treatment adjustment, and no progression to accelerated or blast phase was observed.

• Tolerability: Adverse events generally decreased during dose reduction, although TKI withdrawal-related symptoms, particularly arthralgia and musculoskeletal pain, were not completely eliminated.

• Quality of life: Quality-of-life scores remained largely stable. The speaker attributed this mainly to a ceiling effect, as scores at study entry were already comparable to those of the general population and partly to the persistence of withdrawal-related symptoms.

• Predictive markers: Molecular residual disease dynamics during de-escalation showed potential for predicting subsequent TFR success or failure. Although promising, these findings require further validation, and superiority over abrupt discontinuation has not been established in a randomised comparison.